It is generally accepted by those skilled in the art that the pharmacology of nonsteroidal antiinflammatory drugs, also called NSAIDs, results from the inhibition of prostaglandin G/H synthase in arachidonic acid metabolism. Prostaglandin G/H synthase has also been called cyclooxygenase. Prostaglandin synthase activity results in the formation of prostaglandins and other arachidonic acid metabolites that are important inflammatory agents. These metabolites also have cytoprotective properties and are important for the maintenance of tissue physiology and homeostasis.
It has been recently discovered that there are two distinct isoforms of prostaglandin G/H synthase. The two forms have been called prostaglandin G/H synthase-1 and prostaglandin G/H synthase-2.
Prostaglandin G/H synthase-1 is a constitutive enzyme expressed in a variety of tissues and appears to be the isoform important for physiological and homeostatic processes. In contrast, prostaglandin G/H synthase-2 is upregulated by a variety of agents, including proinflammatorycytokines, endotoxins, mitogens, growth factors and hormones and is downregulated by glucocorticoids.
It is believed that prostaglandin G/H synthase-2 is responsible for the formation of prostaglandins and other arachidonic acid metabolites which contribute to the pathology of inflammation and other diseases.
In general, the nonsteroidal antiinflammatory drugs that are currently used to treat patients inhibit both prostaglandin G/H synthase-1 and prostaglandin G/H synthase-2, and therefore, have mechanism-based side effects due to the inhibition of prostaglandin G/H synthase-1 and the resulting interference with tissue homeostasis.
Compounds which inhibit prostaglandin G/H synthase-2, but have little or no effect on prostaglandin G/H synthase-1 can provide effective antiinflammatory, analgesic and antipyretic activity without causing side effects such as gastrointestinal and renal toxicities which are seen when using traditional nonsteroidal antiinflammatory drugs.